Beta-agonist compounds comprising nitric oxide donor groups and reactive oxygen species scavenger groups and their use in the treatment of respiratory disorders

Abstract

The present invention relates to multifunctional β-agonist compounds comprising a reactive oxygen species scavenger group and a nitric oxide donor, and their use for the treatment of respiratory diseases involving airway obstruction, such as asthma and chronic bronchitis. The invention further relates to methods and devices for administering the compounds.

What is claimed is: 
     
       1. A multifunctional β-agonist compound having reactive oxygen species (ROS) scavenger groups and nitric oxide (NO) donor groups being ROS scavenger and NO donor of Formula 1: 
       
         
           
           
               
               
           
         
       
       or its salt or a solvate thereof or an optical isomer thereof, wherein R 1  is —SNO;
 R 2  is ROS scavenger group or a NO donor group connected to the —NH group via a linker made of C 5 -C 8  cyclic alkyl, or straight or branched C 1 -C 15  alkyl in which one carbon atom is optionally replaced by oxygen or nitrogen, wherein said ROS scavenger group is selected from a nitroxide free radical, alkenyl, sulfhydryl or dithiol moiety in oxidized or reduced form, and aryl, and wherein said NO donor group is selected from —ONO, —ONO 2 , —SNO, and —NONOate or R 2  is C 5 -C 8  cyclic alkyl, or straight or branched C 1 -C 15  alkyl; 
 R 3  and R 4  together form a substituted 5 to 7-membered saturated heterocycle having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein one of said nitrogen atoms being optionally substituted by oxygen to form a nitroxide radical; 
 R 5  is selected from the group consisting of —H and straight or branched chain C 1 -C 15  alkyl; 
 and whereas any of said alkyl groups is optionally substituted with one or more functional groups selected from hydroxyl, bromo, fluoro, chloro, iodo, mercapto thio, cyano, alkylthio, aryl, carboxyl, carbalkoyl, alkenyl, nitro, amino, alkoxyl, or amido; 
 wherein R 2  is said ROS scavenger if said saturated heterocycle does not have the nitrogen atom substituted by oxygen. 
 
     
     
       2. A β-agonist compound according to  claim 1 , wherein said saturated heterocycle is selected from the group consisting of pyrrolidine, oxazolidine, thiazolidine, tetrahydro 1,3-oxazine, 1,3-dioxane, piperidine, 3-thiapiperidine, and 1,3-thiazine. 
     
     
       3. A β-agonist compound according to  claim 1 , wherein the nitroxide free radical is a heterocyclyl moiety having the nitrogen atom within a 5-, 6- or 7-membered ring which optionally contains another heteroatom selected from oxygen and sulfur at position beta to the nitrogen, and which is substituted with methyl or ethyl at positions alpha to the nitrogen. 
     
     
       4. The β-agonist compound of  claim 3 , wherein said heterocyclyl moiety is linked to the β-agonist moiety via sharing of 1 to 2 atoms, or via a linker. 
     
     
       5. A n-agonist compound according to  claim 1 , wherein said ROS scavenger group is selected from the group consisting of the following moieties: 
       
         
           
           
               
               
           
         
       
       wherein X is selected from carbon, oxygen, and sulfur, and n is an integer from 1 to 15. 
     
     
       6. A β-agonist compound according to  claim 1 , wherein R 2  is selected from the following structures: 
       
         
           
           
               
               
           
         
         wherein m is 1-6 and R 8  and R 9  are independently C 1 -C 3  alkyl or —H. 
       
     
     
       7. A β-agonist compound according to  claim 1  having the formula: 
       
         
           
           
               
               
           
         
       
       or its salt of a solvate thereof or an optical isomer thereof; wherein R 1  is SNO;
 R 5  is hydrogen; and 
 R 2  is a moiety selected from a nitroxide free radical having the nitrogen atom within a 5-, 6- or 7-membered saturated ring and which is substituted by up to four methyl groups at positions alpha to the nitrogen, sulfhydryl or dithiol moiety in oxidized or reduced form, —ONO, —ONO 2 , and —SNO, wherein said moiety is connected to the —NH group directly or via a linker made of C 1 -C 6  alkyl, and which linker is 
 
       
         
           
           
               
               
           
         
       
       optionally substituted by one or more phenyl groups. 
     
     
       8. A multifunctional β-agonist compound according to  claim 1  having one of the following structures: 
       
         
           
           
               
               
           
         
       
     
     
       9. A process of preparing an agonist according to  claim 1  being a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or its salt, wherein R 1  is —SNO;
 R 2  is ROS scavenger group or a NO donor group connected to the —NH group via a linker made of C 5 -C 8  cyclic alkyl, or straight or branched C 1 -C 15  alkyl, wherein said ROS scavenger group is selected from a nitroxide free radical, alkenyl, sulfhydryl or dithiol moiety in oxidized or reduced form, and aryl, and wherein said NO donor group is selected from —ONO, —ONO 2 , and —SNO or R 2  is C 5 -C 8  cyclic alkyl, or straight or branched C 1 -C 15  alkyl; 
 and R 5  is selected from the group consisting of —H and straight or branched chain C 1 -C 15  alkyl; 
 and whereas any of said alkyl groups is optionally substituted with one or more functional groups selected from hydroxyl, mercapto, aryl, alkenyl, nitro, and alkoxyl; 
 which process comprises reacting a chiral or non-chiral epoxide or thioepoxide of the formula 
 
       
         
           
           
               
               
           
         
         with an amine of the formula H 2 N—R 2    
         wherein Z is oxygen or sulfur; 
         R 2  is a C 5 -C 8  cyclic alkyl, or straight or branched C 1 -C 15  alkyl linked to a group selected from a nitroxide free radical, alkenyl, sulfhydryl or dithiol moiety in oxidized or reduced form, aryl, —ONO, —ONO 2 , and —SNO; wherein said alkyl is optionally substituted with one or more functional groups selected from hydroxyl, mercapto, aryl, alkenyl, nitro, alkoxyl, C 1 -C 5  alkyl, C 1 -C 5  alkoxy, phenyl, and —CH 2 OH; 
         and R 5  is selected from the group consisting of —H and straight or branched chain C 1 -C 15  alkyl. 
       
     
     
       10. A process according to  claim 9 , wherein said epoxide is prepared from N-benzylphthalimide. 
     
     
       11. A process according to  claim 9 , further comprising converting —SH groups to —SNO groups in the presence of HCl and NaNO 2 . 
     
     
       12. A composition comprising a multifunctional β-agonist compound of  claim 1 , or a salt thereof or a solvate thereof or an optical isomer thereof, for use as a medicament. 
     
     
       13. A pharmaceutical composition comprising a β-agonist compound of any one of  claims 1  to  8 , or a salt thereof or a solvate thereof or an optical isomer thereof. 
     
     
       14. A pharmaceutical composition according to  claim 13 , further comprising carriers, adjuvants, and excipients.